Penicillanic acid derivatives



United States Patent 3,383,383 PENICILLANIC ACID DERIVATIVES Fritz Gapp,Johann Margreiter, and Ekkehard Schmid,

Tirol, Austria, assignors to Biochemie Ges.m.b.H.,

Vienna, Austria N0 Drawing. Filed June 20, 1967, Ser. No. 647,330

41 Claims. (Cl. 260239.1)

The present invention relates to new penicillins and a process for theirproduction.

The invention provides penicillins of general Formula I in which R and Rare identical or different and each signify a hydrogen, fluorine,chlorine, bromine or iodine atom, a lower alkyl radical having 1 to 4carbon atoms, a lower alkoxy radical having 1 to 4 carbon atoms, and Rsignifies a hydrogen atom or a lower alkyl radical having 1 to 4 carbonatoms, and their salts with alkali metals or alkaline earth metals.

The salts of the penicillins of general Formula I are water-soluble andafter parenteral administration they exhibit an extraordinarily longlasting and high concentration in the blood. After intramuscularadministration of these compounds the concentration in the blood amountsto several times the value of Na-penicillin G, whereas the duration ofthe attainable, effective concentration in the blood may be comparedwith that of commercial depot penicillins, e.g., procain-penicillen G.The salts of the penicillins of general Formula I may be administered inthe usual way that depot penicillins are administered.

The new penicillins of the invention have the advantage over commercialdepot penicillins that they do not have the side effects caused by thebasic components of the usual depot penicillins. On administration ofcommercial depot penicillins, great quantities of organic bases arenecessarily administered; some of these organic bases lead to seriousside effects or cause pain reactions.

The compounds of the invention may be used as pharmaceuticals on theirown or in admixture with other susbtances in the treatment of infectiousdiseases in warm-blooded animals.

The present invention further provides a process for the production ofcompounds of general Formula I and their salts with alkali metals oralkaline earth metals, characterized in that a reactive derivative ofisatin-N-alkanecarboxylic acids of general Formula II (:lH-C O OH R3 IIin which R to R have the above significance, is reacted with6-aminopenicillanic acid or its salts in a suitable solvent or solventmixture which is inert under the reaction conditions, and the resultingpenicillins of general Formula I are then optionally converted intotheir salts with alkali metals or alkaline earth metals or are liberatedfrom these.

The acid chlorides are preferably used as reactive derivatives ofisatin-N-alkane-carboxylic acids for the process of the invention.However, other reactive derivatives of isatin-N-alkane-carboxylic acids,e.g., the bromides of said acids, mixed anhydrides, as may be obtainedby reaction of an isatin-N-alkane-carboxylic acid with chlorofonmic acidesters, preferably chloroformic acid ethyl ester, p-nitrophenyl estersof acids of general Formula H and other reactive acid derivatives maylikewise be used.

One preferred method of effecting the process of the invention consistsin that the acid chloride, or a mixed anhydride of a compound of generalFormula II is added in small portions while stirring and stronglycooling with a mixture of ice/common salt to a solution of an alkalimetal salt, preferably the sodium salt, of 6-aminopenicillanic acid in amixture of water and a partially or completely water-miscible solventwhich is inert under the reaction conditions, e.g., dioxanetetrahydrofuran or dimethyl formamide, and the resulting reactionmixture is further stirred at a temperature between l0 and +30 C. at apH value of about 6 to 9 for /z to 2 hours. After the reaction has beencompleted, the penicillins of general Formula I are isolated in mannerknown per so from the reaction mixture, in which they are present assalts, e.g., by extracting with a suitable organic solvent which isinert under the reaction conditions, e.g., ethyl acetate, at an acid pHvalue, washing the extract, e.g., with water, drying and treating theextract with charcoal for purposes of decolouration and evaporating thepurified extract to dryness, and the penicillins of Formula I are thenoptionally converted into their salts in an organic solvent which isinert under the reaction con ditions, e.g., acetone, by reacting withsuitable alkali metal compounds, e.g., sodium or potassium-Z-ethylhexanoate, or suitable alkaline earth metal compounds, e.g., calciumacetate.

In accordance with another embodiment of the process of the invention,the salts of the compounds of general Formula I may be precipitated fromthe extract obtained above by the addition of suitable compounds, e.g.,the alkali metal or alkaline earth metal compounds indicated above.

The compounds of general Formula I may be liberated from the resultingsalts in manner known per se, e.g., by treating with mineral acids.

The term in manner known per se as used herein designates methods in useor described in the literature on the subject.

In the following non-limitative examples, all temperatures are indicatedin degrees centigrade and are corrected.

Example l.Potassium salt of 6-[u-(isatin-N)- acetamido]-penicillanicacid 400 cc. of tetrahydrofuran are added to a solution of 9.7 g. of6-aminopenicil1anic acid and 9.7 g. of sodium bicarbonate in 200 cc. ofwater and 10 g. of isatin-N-acetic acid chloride are added in smallportions during the course of 15 minutes while stirring vigorously andcooling (with ice/ common salt). After the addition has been completed,stirring is continued for 1 hour with cooling. The mixture is thendiluted with water and extracted twice with ether. After the addition of200 cc. of ethyl acetate, the mixture is acidified by the slow additionof phosphoric acid While stirring, the ethyl acetate phase is separated,washing with water, drying over sodium sulphate and treatment withcharcoal are effected. After filtration careful evaporation in a vacuumis effected, Whereby 6-[ot-(isatin N) acetamido] penieillanic acid isobtained in the form of an amorphous yellow orange powder. The potassiumsalt is produced by dissolving the acid in 200 cc. of acetone and adding45 cc. of a l M solution of potassium-Z-ethyl hexanoate in acetone,whereby a yellowish precipitate results, which is filtered with suction,

Washed with acetone and ether and dried in an exsiccator. The potassiumsalt shows an iodometric mg. activity of 1270 U. Water content: 4.95%.[a] =+204 (0.:1 in water).

On storing at room temperature in the air, the potassium salt absorbswater up to a constant value of about 9.8%, which corresponds to acontent of water of crystallization of 3 mols.

Example 2.-Sodium salt of 6-[ot(1S2t[1I1-N)- acetamido1-penicillanicacid Triethyl amine is added dropwise while stirring to a suspension of50 g. of 6-aminopenicillanic acid in 500 cc. of Water and 500 cc. oftetrahydrofuran until the material dissolves. Cooling is then etfectedwith a mixture of ice/common salt and 40 g. of isatin-N-acetic acidchloride are added during the course of 30 minutes while stirring. Theresulting reddish solution is diluted with 500 cc. of water andextracted with 2 liters of ethyl acetate while acidifying with dilutehydrochloric acid. The separated ethyl acetate solution is dried oversodium sulphate and treated with charcoal. After filtration,concentration is effected in a vacuum to 600 cc. On adding a solution of30 g. of sodium-Z-ethyl hexanoate in 100 cc. of absolute ethanol, thesodium salt crystallizes in the form of yellow crystals. The sodium saltis filtered with suction, washed with ethyl acetate and ether and driedin a vacuum at 50. The resulting sodium salt shows an iodometric mg.activity of 1380 U. Water content: 2.7%. [a] =-+23l (c.=1 in water).

(Example 3.6- [u-(isatin-N)-acetamido]-penicillanic acid A solution of 2g. of the potassium salt produced in accordance with Example 1 in 10 cc.of Water is acidified dropwise with 2 N hydrochloric acid while coolingand stirring. The resulting acid is filtered with suction, washedseveral times with cold water and dried over phosphorus pentoxide. Theacid shows an iodometric mg. activity of 1450 U. [cc] =-{22S (c.=0.1butanol). The acid slowly decomposes on heating over 120.

Example 4.-Potassium salt of 6-[a-(5-chloroisatin-N)-acetamido1-penicillanic acid 3.5 g. of S-chloroisatin-N-acetic acidchloride are added in small portions while stirring to a solution cooledwith ice/common salt of 3.2 g. 6-aminopenicillanic acid and 4 g. ofsodium bicarbonate in 60 cc. of water and 100 cc. of tetrahydrofuran.After 30 minutes the mixture is diluted with water, washed with etherand the penicillin is extracted with 100 cc. of ethyl acetate afteracidifying with phosphoric acid. The dried ethyl acetate solution whichhas been treated with charcoal is evaporated to dryness in a vacuum andthe residue is taken up in 100 cc. of acetone. After the addition of 17cc. of a l M solution of potassium-2-ethyl hexanoate in acetone, thepotassium salt results as an almost colourless precipitate, which isfiltered with suction, washed with acetone and ether and dried. Thepotassium salt shows an iodometric mg. activity of 1220 U. [u] =+209(c.=0.5 in water). Water content: 3.0% (theoretically for 1 mol of water3.6%). On standing in the air the water content slowly rises to 3 mols.

Example 5.6-[a-(5-chloroisatin-N)-acetarnido]- penicillanic acid 2 g. ofthe potassium salt produced in accordance with Example 4 are dissolvedin 20 cc. of water and the solution is acidified with 2 N hydrochloricacid while stirring. The precipitated acid is filtered with suction,washed with water and dried. The acid shows an iodometric mg. activityof 1340 U. [a] =+226 (0.:5 in butanol). The acid contains 1 mol ofwater; on heating over 150 decomposition occurs.

Example 6.-Potassium salt of 6-[a-(5-methylisatin-N)-acetamido]-pcnicillanic acid A solution of 4.8 g. ofS-methylisatiu-N-acetic acid chloride in 20 cc. of tetrahydrofuran isadded dropwise at -10 while stirring to a solution of 4.4 g. of6-arninopenicillanic acid and 4.4 g. of sodium bicarbonate in 40 cc. ofwater and 20 cc. of tetrahydrofuran. After stirring for 30 minutes themixture is diluted with water, washed with ether and the penicillin isextracted with cc. of ethyl acetate after acidifying with phosphoricacid. The ethyl acetate phase which has been washed with water istreated with charcoal and then carefully evaporated in a vacuum. Theresidue is taken up in 100 cc. of acetone and 20 cc. of a 1 Mpotassium-Z-ethyl hexanoate solution in acetone are added, whereby thepotassium salt results as light orange precipitate. The precipitate isfiltered with suction, washed with acetone and ether and dried. Thepotassium salt shows an iodometric mg. activity of 1320 U. [a] =+201 (0.1 in water). Water content: 4%.

Example 7.-6- [a-(S-methylisatin-N -acctamido] penicillanic acid Thefree acid is precipitated with dilute hydrochloric acid from the aqueoussolution of the potassium salt produced in accordance with Example 6.After washing out with water and drying over phosphorus pentoxide thefree acid shows an iodometric mg. activity of 1385 U. [a] :+226 (c.=0.5butanol).

Example 8.-Potassium salt of 6-[a-(5,6-dimethylisatin- N) -acetamido]-penicillanic acid 2.5 g. of 5,6dimethylisatin-N-acetic acid chlorideare slowly added while stirring and cooling with ice to a solution of2.5 g. of 6-aminophenicillanic acid and 2.5 g. of sodium bicarbonate in50 cc. of water and 50 cc. of tetrahydrofuran. After stirring for 1 hourthe mixture is diluted with water and the penicillin is extracted withbutyl acetate after acidifying by the careful addition of phosphoricacid. After drying the butyl acetate solution over sodium sulphate andadding 10 cc. of a 1 M solution of potassium-Z-ethyl hexanoate inacetone the potassium salt precipitates in the form of fine needles. Theresulting potassium salt shows an iodometric mg. activity of 1370 U.[a]- =+187 (c.=0.5 in water).

The penicillins indicated in the following Table 1 are produced inaccordance with the process described in Examples 1, 2, 4, 6 and 8.

TABLE 1 Iodomctrlc [aln Pcnlcillins activity, (c.=0.5ln

U/mg. H2O), C.

Sodium salt of 6-[w(4-chloroisatin-N)-aeetamido]-penicillanic acid 1,015 +166. 5 Sodium salt of Ha-(fi chloroisatin-Nyacetamido1-penicillanicacid 1, 020 +101. 0 Sodium salt of6-[a-(4-bromoisatln-N)acctamido1-penieillanic acid 740 +187. 0 Potassiumsalt of 6-[a-(&bromoisatin-N)- acctamidol-penlcillanic acid 1,010 +163.0Sodium salt of Ma-(5-fluoroisatin-N)aeetamidol-penicillanic acid 1, 180+151. 0 Sodium salt of 6-[a-(5-lodoisatin-N)-acctamido1-penieillanicacid 910 +134. 0 Sodium salt of6[a-(6-methylisatin-N)-acetamido1-penicillanic acid 1,050 +173.0Potassium salt 01 6[a-(7-methylisatin-N)- acetamido]-penicillanic acid1, 305 +152. 0 Potassium salt of 6-[a-(5-methoxyisatin-N)-acctamido1-penicillanic acid 1, 230 1 +145. 0 Sodium salt offi-[a-(ibromo-tS-methylisatin- N)-acetan1ido]-pcnicillanic acid 1,003+1550 Sodium salt of 6-[D,L-a-(lsatin-N)-propionamido]-penicillanic acid1,190 +1425 Sodium salt of 6-[D,L-a-(5-mcthylisatin-N)-propionamidol-penicillanic acid 1,310 +1450 Sodium salt ofS-[D,L-a-(aehlorolsatin-Ny propionarnido1-penicillanic acid 975 +140. 0Sodium salt of 6-[D,L-a-(&bromoisatin-N)- propionarnido1-penicillanicacid 940 +125. 0 Potassium salt 6-[a-(5,7-dimethyl-N)-acetamidol-penicillanie acid 1,355 +105. 0 Sodium salt of 6-[a-(SethIisatin-Nyacetamidol-penicillanic acid 1,220 +1830 The reactivederivatives of isatin-N-alkane-carboxylic What is claimed is: acids ofgeneral Formula II used as starting materials for 1. A compound selectedfrom the group consisting of a the process of the invention may beproduced from the compound of formula: corresponding free acids inmanner known per se; for ex- R1 ample the acid chlorides are produced byheating the free 5 acid for to minutes with a ten-fold quantity pervolume of thionyl chloride. The free is-atin-N-alkane- O carboxylicacids of general Formula II have already been described in theliterature or may be obtained in manner R2 known per se, e.g., asdescribed in Ber. 61, 944, and J. (FH CONH (|3H OH C(CHa) 1O Chem. Soc.1934, 1512. R3

The following Tables 2 and 3 indicate the physical in which R and R arethe same or ditferent and each is data of some of the acids of generalFormula II and their hydrogen, fluorine, chlorine, bromine or iodine,lower acid chlorides. alkyl of 1 to 4 carbon atoms, or lower alkoxy of 1to 4 TABLE 2 Analysis, percent Appearance, Melting Molecular Compoundrecrgystallized ng in Formula weight Calculated Found rom- C H C H (a)(b) (g) Isatin-N-acetic acid 1 Orange needles (water) 2 209-211 C1OH NO4205. 17 4-chlcroisatin-N-acetic acid.- Orange leaflets (ethanol).ClQHfiClNO4 239.62 50.12 2.52 50.08 2 77 6-chloroisatin-N-acetic acid.Yellow needles (dilute eth ol CwHeClNoi 239.62 50.12 2 52 50.12 2 68S-DrOmoisatin-N-acetic acid... Yellrow-olsange crystals (diluteCwlieBrNoi 284.08 42.28 2 13 42.34 2 26 e ano 5-nitroisatin-N-aceticacid Yellow needles (dilute ethanol) 3 211-213 C HaN oi 251. 185-1nethylisatin-N-acetic acid. Orange needles (glacial acetic acid)..232-234 C11H0NO4 219.20 60.27 4.14 60.20 4.20 7-methylisatin-N-aceticacid Orange tablets (ethanol) C1lHflNO4 219.20 60.27 4.14 60.16 4.225-1nethoxyisatin-N-acetic aci Red-brown needles (ethanol).. C11H9N05235.20 56.17 3.86 55.90 3.85 Isatin-N-a-propionlc acid... Red crystals(dllute ethanol)... 174-176 C H9NO4 219.20 60.27 4.14 59.88 4. 245-chloroisatin-N-a-propionic Orange crystals (glacial acetic aci 197-200CuHsClNO4 253.65 52.09 3.18 52.00 3.47 5-bromoisatin-N-a-propionicacid.- Red crystals (dllute ethanol) 219-225 C11HBBINO4 298.11 44.322.70 44.47 2.92 G-methylisatln-N-acetic a cld.- Orange needles (diluteethanol). 235-237 C11H9NO4 219.20 60.27 4.14 60.66 4.125-methylisatin-N-a-propionic aci Orange needles (water) 180-184 CrzHnNOr233.23 61.80 4. 61.77 4.88 5-iodoisatin-N-acetic acid Orange crystals(water)-.... 225-228 cmHuNo. 331.08 36.28 1.83 36.30 1.895-fluoroisatin-N-aeetic acid Yellow-brown needles (water) 178-180OlOHflFNOl 223.16 53.82 2.71 53.86 2.81 5-bromo-6-rnethylisatin-N-aceticacid..... Yellow needles (et|.anol) 255-258 O lIsBrNOi 298.11 44.32 2.7044.60 2. 81 5-chloroisatiu-N-acetie acid Yellow needles (water)....202-205 CwHeClNO; 239. 62 50.12 2. 52 50.17 2. 75 4-bromoisatin-N-aceticacid. Orange leaflets (ethanol) 284.08 42. 28 2.13 42.52 2. 21S-ethylisatin-N-acetic acid Orange leaflets (water).. 233.23 61.80 4.7561.62 4.92 5,6-dimethylisatin-N-acetic acid.-. Yellow needles(etha'nol).- 233.23 61 4.75 61.56 4.85 5,7-dimetl1ylisatin-N-aceti0 acidRed crystals (ethanol) C12H11N04 233.23 61 8O 4. 75 62.38 4.79

1 Langenbeck, Ber. 61, 944. 2 Lit.: 206-207. 3 Lit.: 207.

TABLE '3 Analysis, percent Appearance, Melting Molecular Compoundrecriystallizcd po irg in Formula weight Calculated Found O H 0 HIsatin-N-acetic acid chloride 1 Yellow needles (petroleum ether)--...139-141 CwHeClNO 223. 62 4-chloroisatin-N-acetic acid chloride. Yellowleaflets (benzene) 144-146 C10H5C12N03 258.07 5-chloroisatin-N-aceticacid chloride. Yellow needles (benzene) 178-180 owrnouNo... 258.076-chloroisatin-N-acetic acid chloride. Yellow crystals (benzene) 182-183C10H Cl2N0 258. 07 5-bromoisatin-N-acetic acid chloride Yelliw) needles(benzene/petroleum 157-159 C10H5BrClN0 302.53

e er S-nitroisatin-N-acetic acid chloride Yclllil)w)needlcs(benzene/petroleum 141-143 C10H5C1N 20 268. 62

et er 5-methylisatin-N-acetic acid chloride....- Orafige) needles(benzene/petroleum 160-162 CUHBCINOI; 237.65 55.59 3.39 55.71 3.57

er 7-methylisatin-N-acetic acid chloride..... Red crystals (benzene)97-102 CuHsC1NO3 237.65 55.59 3. 39 55.88 3.57 ISEllJlll-N-a-DIOPlOIIlCacid chloride Or:gl1ge)needles (benzene/petroleum 109-112 CHHBCINOQ237.65 55.59 3.39 55.69 3.49

e er 5-chloroisatin-N-a-propionic acid ehlororefigineedles(benzene/petroleum 118-120 C11H Cl2NO 272. 10 48. 55 2. 59 48. 64 2. 69

ide. e er 5-bromoisatin-N-a-propionic acid chlor- Oragge prisms(benzene/petroleum 127-129 C11H BrClNO 316.56 41.74 2.23 42.24 2.42

ide. et er fi-rnethylisatin-N-acetic acid chloride...-. Yetlgllpwneedles (benzene/petroleum 136-140 C11HsClNO;.-.... 237.65 55.59 3.3955.95 3.60

e er 5-methylisatin-N-Q-propionic acid chol- Red oil C12H10C1NO3 251.6757.27 4.00 57.56 4.35

ride. 5-iodoisatin-N-acetic acid chloride OraEge) crystals(benzene/petroleum -155 CmH5ClIN0 349.52 34.36 1.44 34.72 1.49

ct er 5-fluoroisatin-N-acetic acid chloride Orange prisms (benzene)188-190 C1nH5ClFNO3 241.61 49.71 2.08 49.95 2.235-bromo-6-methylisatin-N-acetic acid Yeltllpwfrystals (benzene/petroleum186-188 C11H1BrClNO3...- 316.55 41.74 2.23 41.65 2.46

chloride. e er. 4-bromoisatin-N-acetic acid chloride Yellow prisms(benzene) 163-165 CmHiBrClNO3... 302.53 39.71 1.67 40.10 1.845-ethylisatin-N-acetic acid chloride. Oragge needles (benzene/petroleum88-91 O12H1flC1NO3- 251. 67 57. 27 4. 00 57. 55 4.12

ct er 5,ddirnethylisatin-N-acetic acid chlo- Yellow needles (benzene)174-176 C12Hl0ClNO3 251. 67 57. 27 4. 00 57.61 4.06

ride. 5,7-dimethylisatin-N-acetic acid chloride. Relhnefdles(benzene/petroleum 154-156 Cl2HiuC1NO3-- 251.67 57. 27 4. 00 57.60 4.03

e er

l Langenbeck, Ber. 61, 944.

carbon atoms, and R is hydrogen or lower alkyl of I to 4 carbon atoms,and the pharmacologically acceptable alkali metal or alkaline earthmetal salts thereof.

2. A compound according to claim 1, in which the compound is thepotassium salt of 6-[u-(isatin-N)-acetamido]-penicillanic acid.

3. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[a-(isatiu-N)-acet amido]-penicillanic acid.

4. A compound according to claim 1, in which, the compound is6-[a-(isatin-N)-acetamido]-penicillanic acid.

5. A compound according to claim 1, in which the compound is thepotassium salt of 6-[oc-(5-Chl0f0- isatin-N -acetamido] -penicillanicacid.

6. A compound according to claim 1, in which the compound is6-[a-(S-chloroisatin-N)-acetamido]-penicil lanic acid.

7. A compound according to claim 1, in which the compound is thepotassium salt of 6-[a-(5-methylisatin-N)-acetamido]-penici1lanic acid.

8. A compound according to claim 1, in which the compound is thepotassium salt of 6-[e-(5,6-dimethylisatin-N)-acetamido1-penicillanicacid.

9. A compound according to claim 1, in which the compound is 6 [a(5,6-dimethylisatin-N)-acctamidopenicillanic acid.

10. A compound according to claim 1, in which the compound is6-[u-(4-chloroisatin N)-acetamido]-penicillanic acid.

11. A compound according to claim 1, in which the compound is the sodiumsalt of 6-La-(4-chloroisatin-N)- acetamido]-penicillanic acid.

12. A compound according to claim 1, in which the compound is6-[oz-(o-chloroisatin-N)-acetamido]-penicillanic acid.

13. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[a-(6-chloroisatin-N)- acetamido1-penicillanic acid.

14. A compound according to claim 1, in which the compound is6-[a-(4-bromoisatin-N)-acetamido]-penicil lanic acid.

15. .A compound according to claim 1, in which the compound is thesodium salt of 6-[a-(4-brom0isatin-N} acetamido]-penicillanic acid.

16. A compound according to claim 1, in which the compound is6-[a-(S-brOmOisatin-N)-acetamido]-penicil lanic acid.

17. A compound according to claim 1, in which the compound is thepotassium salt of 6-[oc-(5-bIOII10- isatin-N)-acetamido]-penicillanicacid.

18. A compound according to claim 1- in which the compound is6-[a-(S-fiuoroisatin-N)-acetamido]-penicillanic acid.

19. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[a-(5-fiuoroisatin-N)- acetamido]-penicillanic acid.

20. A compound according to claim 1, in which the compound is6-[a-(S-iodoisatin-N)-acetamido]-penicillanic acid.

21. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[a-(5-iodoisatin-N)- acetamido]-penicillanic acid.

22. A compound according to claim 1, in which the compound is6-[a-(6-methylisatin-N)-acetamido]-penicillanic acid.

23. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[a-(6-methylisatin-N) acetamido]-penicillanic acid.

24. A compound according to claim 1, in which the compound is 6- i a-(7-methylisatin-N -acetamido -penicillanic acid.

25. A compound according to claim 1, in which the compound is thepotassium salt of 6-[u-(7-methylisatin-N -acetamido -penicillanic acid.

26. A compound according to claim 1, in which the compound is6-[a-(i-methoxyisatin-N)-acetamido]-penicillanic acid.

27. A compound according to claim 1, in which the compound is thepotassium salt of 6-[a-(5-methoxy isatin-N)-acetamido]-penicillanicacid.

28. A compound according to claim 1, in which the compound is6-[a-(5-bromo 6 methylisatin-N)-acetamido1-penicillanic acid.

29. A compound according to claim 1' in which the compound is the sodiumsalt of 6-[a-(5-bromo-6-methylisatin-N) -acetarnido] -penicillanic acid.

30. A compound according to claim 1, in which the compound is6-[D,L-a-(isatin-N)-propionamido]--penicillanic acid.

31. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[D,L-u-(isatin-N)-propionamido1-penicillanic acid.

32. A compound according to claim 1, in which the compound is 6-[D,L a(S-methylisatin-N)-propionamido]-penicillanic acid.

33. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[D,L-a-(5-methylisatin-N -propionamido] -pcnicillanic acid.

34. A compound according to claim 1, in which the compound is6-[D,L-a-(S-chloroisatin-N)-propionamido] penicillanic acid.

35. A compound according to claim 1, in which the compound is the sodiumsalt of 6[D,L-a-(5-chloroisatin-N)-propionmido]-penicillanic acid.

36. A compound according to claim 1, in which the compound is6-[D,L-a-(S-bromoisatin-N)-propionamido]- penicillanic acid.

37. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[D,L-a-(S-bromoisatin-N)-propionamido]-penicillanic acid.

38. A compound according to claim 1, in which the compound is6-[e-(SJ-dimethyI-N)-acetamido]-penicillanic acid.

39. A compound according to claim 1, in which the compound is thepotassium salt of 6-[a-(5,7-dimethyl-N)- acetamidoJ-penicillanic acid.

40. A compound according to claim 1, in which the compound is6-[a-(S-ethyIiSatin-N)-acetamido]-penicillanic acid.

41. A compound according to claim 1, in which the compound is the sodiumsalt of 6-[u-(5-ethylisatin-N)- acetamido]-penicillanic acid.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OFFORMULA: